Genetic Mechanisms Program Summary The scientific goals of the Genetic Mechanisms Program are to define and understand the genetic changes that occur during cancer development, to understand the genesis of those changes, and to use gene transfer technology to treat cancer. These goals include defining the specific changes that drive tumor initiation and progression, lead to resistance to tumor treatment, and influence cancer susceptibility. To achieve these goals, we feature strong research programs focused on the following Aims: 1) To identify cancer susceptibility genes, DNA mutators, and drivers of metastasis to develop new biomarkers for cancer progression and drug targets for therapeutic intervention; 2) To understand the mechanisms that maintain genome stability, including pathways that control replication stress and DNA damage tolerance; and 3) To develop a new generation of viral and nonviral cancer therapeutics that will be tested in preclinical animal models. The Genetic Mechanisms Program is a basic science program led by Anja-Katrin Bielinsky, PhD, and new co-leader Masato Yamamoto, MD, PhD, and has 43 members, representing 19 departments and 8 schools or colleges. Dr. Bielinsky oversees the early phases of translation, and Dr. Yamamoto assists with later phases and facilitates active collaborations with clinicians outside GM who are experts in clinical trials. For the last budget year, GM members were supported by $2.9 million in direct costs from the National Cancer Institute, other NIH funding totaled $7.2 million, total peer-reviewed funding was $10.95 million, and cancer-related funding from all sponsored sources totaled $15.2 in direct costs. Since 2013, Program members have published 634 papers, 17% of which resulted from intraprogrammatic collaborations, 20% from interprogrammatic collaborations, and 85% from external collaborations. Over the past funding cycle, we enhanced our team-building efforts to promote research in areas that span multiple themes. Uncovering the mechanisms that promote drug resistance in solid tumors is one such area that aligns strongly with the Masonic Cancer Center Strategic Plan Scientific Priority for Growth (SPG2) of enhancing functional genomics strategies to further our understanding of cancer and develop new therapeutic avenues. Major accomplishments include 1) validation of novel biomarkers that predict progression-free survival in solid tumors, 2) uncovering druggable targets in osteosarcoma, 3) generating functional genomics pipelines that allow for the systematic identification of drug- resistance pathways, and 4) generating a second-generation suite of oncolytic viruses that will improve treatment of patients in our catchment area. The Masonic Cancer Center has provided substantial value to the Program, including access to shared resources, recruitment of new faculty, funding of 26 pilot projects for nearly $1M, annual research retreats, monthly Program meetings, weekly seminars, and a weekly newsletter to facilitate collaborations.